IOZK - Immunologisch Onkologisches Zentrum Köln
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Current status of immunotherapy for the treatment of biliary tract cancer.
Okt. 2013 | Takahashi, Ryuji; Yoshitomi, Munehiro; Yutani, Shigeru; Shirahama, Takahisa; Noguchi, Masanori; Yamada, Akira; Itoh, Kyogo; Sasada, Tetsuro
Biliary tract cancer (BTC) is one of the most aggressive malignancies. Although various promising regimens of chemotherapeutic and/or molecular targeted agents have been developed, further treatment modalities, including immunotherapies, still remain to be established for refractory patients who are unresponsive to or relapse after currently available therapeutic options for BTC. Recently, several clinical trials of immunotherapies, including peptide-based vaccines and dendritic cell (DC)-based vaccines, have been reported with promising results. Here we summarize the data from phase I or phase II clinical trials of immunotherapies for BTC. In particular, we introduce our novel immunotherapeutic approach called personalized peptide vaccine (PPV), in which HLA-matched peptides were selected and administered based on the pre-existing host immunity before vaccination, for the treatment of advanced BTC. Further clinical trials would be recommended to prove clinical benefits of these novel immunotherapeutic approaches. Recently concomitant treatments, such as chemotherapies and immune checkpoint blockade, have been reported to enhance the therapeutic effects of cancer immunotherapies through multiple coordinated immune mechanisms. Additional therapies in combination with immunotherapies could produce synergistic effects in the treatment of advanced BTC. PMID 23376808

Dendritic cell-based immunotherapy targeting synthesized peptides for advanced biliary tract cancer.
Aug. 2013 | Kobayashi, Masanori; Sakabe, Tomoyo; Abe, Hirofumi; Tanii, Mitsugu; Takahashi, Hidenori; Chiba, Asako; Yanagida, Eri; Shibamoto, Yuta; Ogasawara, Masahiro; Tsujitani, Shun-ichi; Koido, Shigeo; Nagai, Kazuhiro; Shimodaira, Shigetaka; Okamoto, Masato; Yonemitsu, Yoshikazu; Suzuki, Noboru; Nagaya, Masaki; ,
The aim of this retrospective study was to clarify the safety and efficacy of dendritic cell (DC)-based immunotherapy targeting synthesized peptides, Wilms tumor 1 (WT1) and Mucin 1, cell surface associated (MUC1) for biliary tract cancers (BTCs). PMID 23877328

A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors.
Sep. 2011 | Lepisto, Andrew J; Moser, Arthur J; Zeh, Herbert; Lee, Kenneth; Bartlett, David; McKolanis, John R; Geller, Brian A; Schmotzer, Amy; Potter, Douglas P; Whiteside, Theresa; Finn, Olivera J; Ramanathan, Ramesh K
Pancreatic and biliary cancers are relatively resistant to chemotherapy and radiation and may therefore provide an opportunity for testing the potential of immunotherapy. MUC1 is an epithelial cell glycoprotein that is highly overexpressed and aberrantly glycosylated in many adenocarcinomas, including pancreatic tumors, providing a tumor specific antigen and target. We performed a Phase I/II clinical trial of a MUC1 peptide-loaded DC vaccine in 12 pancreatic and biliary cancer patients following resection of their primary tumors. The primary endpoints were vaccine toxicity and immunogenicity and the secondary endpoint was clinical outcome. The vaccine was well tolerated and no toxicity was observed. Three patients had pre-existing MUC1 antibody responses that remained stable post vaccination. MUC1-specific T cell responses were difficult to evaluate due to increases in activity of all CD8 and CD4 T cells following each vaccination. Prior to vaccination, patients entered onto this trial had a significantly higher percentage of FoxP3+CD4+ T cells compared to age matched healthy controls. The percentage of these cells also increased transiently following each injection, returning to baseline or below before the next injection. Vaccinated patients have been followed for over four years and four of the twelve patients are alive, all without evidence of recurrence. Study of the immune parameters in long-term survivors several years after vaccination may yield the sought after immune correlates of clinical responses that analysis of immune responses shortly after vaccination has not revealed. PMID 19129927

Successful immunological treatment of gallbladder cancer in India--case report.
Aug. 2006 | Khan, Jamal A; Yaqin, Sharmin
Gallbladder cancer has a poor outcome because of its anatomy and location. Often, the diagnosis is made very late due to its silent course. Post-operated cases do respond to chemotherapy but the survival is counted in months and the quality of life is further hampered due to toxicity of drugs. Immunotherapy holds good promise in non-responding cancers treated by conventional chemotherapeutic agents. Among various therapies, dendritic cell therapy is growing at rapid pace due to its acceptable rationale. It has been utilized in treating successfully resected stage III (T2, N1, M0) gallbladder cancer in one of our patients. A 48 years old lady treated with this therapy is free of metastasis with ten doses of autologous dendritic cell vaccine constructed by utilizing resected tumor lysate antigen. She has received ten doses of therapy in 14 months of her treatment. This therapy has proven to be safe and without apparent side effects. The positive clinical response obtained supports that autologous dendritic cell-based immunotherapy is a promising therapeutic approach for refractory gallbladder cancers. PMID 16909473

Intrahepatic cholangiocarcinoma with lymph node metastasis successfully treated by immunotherapy with CD3-activated T cells and dendritic cells after surgery: report of a case.
Mai 2006 | Higuchi, Ryota; Yamamoto, Masakazu; Hatori, Takashi; Shimizu, Koichi; Imai, Kenichirou; Takasaki, Ken
Intrahepatic cholangiocarcinoma (ICC) with lymph node (LN) metastasis is generally associated with a poor prognosis. However, we treated ICC with LN metastasis successfully by surgery and postoperative immunotherapy in a 59-year-old woman. The immunotherapy consisted of CD3-activated T cells and tumor lysate- or peptide-pulsed dendritic cells. Pathological examination confirmed a diagnosis of moderately differentiated adenocarcinoma with LN metastasis and portal vein invasion. The patient has been alive without recurrence for 3 years 6 months since her operation. PMID 16715430

Prognostic significance of CD83 positive, mature dendritic cells in the gallbladder carcinoma.
Juli 2005 | Furihata, Makoto; Ono, Yuko; Ichikawa, Kazuhito; Tomita, Shigeki; Fujimori, Takahiro; Kubota, Keiichi
Dendritic cells (DCs) are very potent antigen-presenting cells that play an essential role in the primary immune response to carcinoma. Tumor-infiltrating DCs have been found to be clinically significant in many human malignancies such as colon, stomach, lung, breast and hepatic carcinoma. However, clinical significance of activated and/or immature DCs in gallbladder carcinoma has not been reported yet. Thus, we immunohistochemically evaluated CD83+ DCs and CD1a+ DCs of cancerous and peritumoral area in 29 cases of resected gallbladder. In the results, CD83(+) DCs were significantly fewer in cancerous area than that in peritumoral area (1.55/hpf vs. 4.26/hpf, p=0.0047), but the numbers of CD1a(+) DCs did not differ (p=0.075). In addition, we defined a CD83 index as CD83(+) DCs/(CD83(+) DCs plus CD1a(+) DCs), and analyzed the relationship between CD83 index and clinicopathological factors. The group with a higher CD83 index (index >0.316) showed significantly better prognosis than the group with a lower CD83 index (index < or =0.316) in cancerous and peritumoral areas. In conclusion, we suggest the importance of tumor-infiltrating CD83(+) DCs as a useful prognostic factor for patients with gallbladder carcinoma. PMID 16012714

Effects of dendritic cells transfected with full length wild-type p53 and modified by bile duct cancer lysates on immune response.
Feb. 2005 | Sun, Hua-Wen; Tang, Qi-Bing; Tang, Chong; Zou, Sheng-Quan
Dendritic cells (DCs) are the most potent antigen-presenting cells and are actively used in cancer immunotherapy. Wild-type p53 can be recognized as an antigen and can induce specific cytotoxic T lymphocytes (CTLs) in the host body. The aim of this study was to investigate the effects of DCs transfected with full length wild-type p53 and modified by bile duct lysates on immune response. PMID 15730935

Dendritic cells, T-cell infiltration, and Grp94 expression in cholangiocellular carcinoma.
Juli 2004 | Takagi, Satoshi; Miyagawa, Shin-Ichi; Ichikawa, Eri; Soeda, Junpei; Miwa, Shiro; Miyagawa, Yusuke; Iijima, Satoshi; Noike, Terumasa; Kobayashi, Akira; Kawasaki, Seiji
Although dendritic cells (DCs) play an important role in tumor immunity, there have been no reports on their role in cholangiocellular carcinoma (CCC). In 26 formalin-fixed, paraffin-embedded tissue sections from patients with CCC, cells positive for CD83 (a marker of mature DCs), CD1a (a marker of immature DCs), and CD8 and CD4 (T cell markers) were counted, and expression of glucose-regulated protein (grp) 94, which is considered to participate in the maturation of DCs, was evaluated by immunohistochemistry and Western blot analysis to study the relationship between their expression and patients' disease outcome. The number of CD83-positive DCs at the invasive margin of CCCs correlated significantly with the number of CD8-positive or CD4-positive T cells in the cancerous region and was significantly higher in grp94-positive cancer than in grp94-negative cancer (P = 0.0006). CD83-positive patients (positive cells in invasive margin > 12.4/field) had both a significantly lower incidence of lymph node metastasis (23.1% vs 69.2%; P = 0.0206) and a better outcome than CD83-negative patients (P <0.001). We conclude that mature DCs are distributed predominantly at the invasive margin of cancers, and a significantly higher number of mature DCs at the invasive margin are observed in patients with grp94-positive cancer cells. Mature DCs may enhance CD8- and CD4-positive cell infiltration into cancers and improve prognosis in patients with CCC, due in part to abatement of lymph node metastasis. PMID 15257553

Clinical significance of immune cell infiltration within gallbladder cancer.
Okt. 2003 | Nakakubo, Y; Miyamoto, M; Cho, Y; Hida, Y; Oshikiri, T; Suzuoki, M; Hiraoka, K; Itoh, T; Kondo, S; Katoh, H
To investigate the pathophysiological significance of infiltrating antitumour immune cells, we evaluated the quantity of immune cell intratumoral infiltration in 110 surgically resected gallbladder specimens by immunohistochemistry. We examined 45 cases of gallbladder cancer and 65 cases of benign gallbladder diseases for CD4(+) T cells, CD8(+) T cells, natural killer cells (NKCs), and dendritic cells (DCs). High levels of CD4(+) T cell, CD8(+) T cell, NKC, and DC infiltration were recognised in 51.1% (23 out of 45), 37.8% (17 out of 45), 33.3% (15 out of 45), and 48.9% (22 out of 45) of cancer specimens, respectively. High numbers of infiltrating CD4(+) and CD8(+) T cells correlated with decreasing tumour invasion, and high numbers of infiltrating DCs correlated with decreasing lymph-node tumour metastasis. Furthermore, increased infiltration of CD4(+) and CD8(+) T cells and DCs exhibited a significant correlation with prolonged survival. NKC infiltration, however, did not correlate with any of the clinicopathological factors examined. Additionally, high levels of infiltration were not identified in specimens from benign diseases, consistent with the cancer-specific activity of CD4(+) and CD8(+) T cells and DCs. In this study, we demonstrate that CD4(+) and CD8(+) tumour-infiltrating lymphocyte and DCs, but not NKCs, are important factors in the accurate prognosis of survival after surgical removal of gallbladder adenocarcinoma. PMID 14583778

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